Hypertrophic cardiomyopathy (HCM) is a common genetic. Imaging

Transcription

1 Imaging Mitral Valve Abnormalities Identified by Cardiovascular Magnetic Resonance Represent a Primary Phenotypic Expression of Hypertrophic Cardiomyopathy Martin S. Maron, MD; Iacopo Olivotto, MD; Caitlin Harrigan, BA; Evan Appelbaum, MD; C. Michael Gibson, MD; John R. Lesser, MD; Tammy S. Haas, RN; James E. Udelson, MD; Warren J. Manning, MD; Barry J. Maron, MD Background Whether morphological abnormalities of the mitral valve represent part of the hypertrophic cardiomyopathy (HCM) disease process is unresolved. Therefore, we applied cardiovascular magnetic resonance to characterize mitral valve morphology in a large HCM cohort. Methods and Results Cine cardiac magnetic resonance images were obtained in 172 HCM patients (age, years; 62% men) and 172 control subjects. In addition, 15 HCM gene-positive/phenotype-negative relatives were studied. Anterior mitral leaflet (AML) and posterior mitral leaflet lengths were greater in HCM patients than in control subjects (26 5 versus 19 5 mm, P 0.001; and 14 4 versus 10 3 mm, P 0.001, respectively), including 59 patients (34%) in whom AML length alone, posterior mitral leaflet length alone, or both were particularly substantial ( 2 SDs above controls). Leaflet length was increased compared with controls in virtually all HCM age groups, including young patients 15 to 20 years of age (AML, 26 5 versus 21 4 mm; P ) and those 60 years of age (AML, 26 4 versus 19 2 mm; P 0.001). No relation was evident between mitral leaflet length and LV thickness or mass index (P 0.09 and P 0.16, respectively). A ratio of AML length to LV outflow tract diameter of 2.0 was associated with subaortic obstruction (P 0.001). In addition, AML length in 15 genotype-positive relatives without LV hypertrophy exceeded that of matched control subjects (21 3 versus 18 3 mm; P 0.01). Conclusions In HCM, mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease, and are an important morphological abnormality responsible for LV outflow obstruction in combination with small outflow tract dimension. These findings suggest a novel role for cardiac magnetic resonance in the assessment of HCM. (Circulation. 2011;124:40-47.) Key Words: cardiomyopathy, hypertrophic magnetic resonance imaging mitral valve Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease in which the predominant phenotypic expression is left ventricular (LV) hypertrophy. 1 5 Previous reports of selected HCM populations studied at autopsy or after operative excision of the mitral valve have suggested that the mitral valvular apparatus may be structurally abnormal in some patients. 6 However, data regarding the prevalence, functional characteristics, and significance of mitral valve abnormalities in a consecutive, clinically assessed HCM cohort are unavailable. Efforts at characterizing mitral leaflet size and length quantitatively with 2-dimensional echocardiography proved disappointing, although it is possible to appreciate greatly elongated leaflets in qualitative terms on routine clinical evaluations. 7 However, cardiovascular magnetic resonance (CMR) imaging, with its high spatial and temporal resolution, provides a unique opportunity to characterize mitral valve structure in vivo Therefore, in the present investigation, we used advanced imaging CMR to define morphological abnormalities of the mitral valve and to determine their relation to a number of demographic and clinical variables in a large HCM cohort. Editorial see p 9 Clinical Perspective on p 47 Methods Selection of Patients We prospectively studied 172 consecutive HCM patients with CMR who presented to HCM referral centers at Tufts Medical Center Received September 1, 2010; accepted April 4, From the Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, MA (M.S.M., C.H., J.E.U.); Referral Center for Myocardial Diseases, Azienda Ospedaliera Universitaria Careggi, Florence, Italy (I.O.); PERFUSE Core Laboratory and Data Coordinating Center, Harvard Medical School, Boston, MA (E.A., C.M.G., W.J.M.); Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.A., C.M.G., W.J.M.); and Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (J.R.L., T.S.H., B.J.M.). Guest Editor for this article was Catherine M. Otto, MD. Correspondence to Martin S. Maron, MD, Tufts Medical Center, No. 70, 800 Washington St, Boston, MA mmaron@tuftsmedialcenter.org 2011 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 Maron et al Mitral Valve Abnormalities in HCM 41 Figure 1. The spectrum of mitral leaflet abnormalities in 6 hypertrophic cardiomyopathy (HCM) patients shown in left ventricular (LV) 3-chamber diastolic long-axis cardiac magnetic resonance images. Thick arrows denote anterior mitral leaflet (AML); thin arrows, posterior mitral leaflet (PML). A, An elderly man with an extraordinarily long AML measuring 33 mm; the PML is of normal length (although not well visualized in this frame). B, A 16-year-old boy with elongated PML (25 mm), 2-fold longer than the matched control subject (not shown here); the AML is of normal length. C, A 14-yearold boy with elongation of both the AML (33 mm) and PML (21 mm). D, A 34-yearold man with only mild ventricular septal (VS) thickness of 18 mm but particularly long AML (35 mm). E, A 31-year-old woman showing massive septal hypertrophy (thickness, 31 mm) but normal AML length. F, A 57-year-old man with preclinical HCM (myosin binding protein C mutation) and normal LV wall thickness of 9 mm (asterisk) but greatly elongated AML (25 mm); the PML is of normal length. AO indicates aorta; LA, left atrium. (Boston, MA) and the Minneapolis Heart Institute (Minneapolis, MN) for clinical evaluation from April 2004 to December Diagnosis of HCM was based on demonstration by CMR of a nondilated, hypertrophied LV (maximum wall thickness 15 mm) in the absence of another cardiac or systemic disease that could produce the magnitude of hypertrophy evident. 3,4 In addition, 172 patients referred to the Minneapolis Heart Institute for evaluation over the same time period in whom there was no clinical or CMR evidence of cardiovascular or valvular heart disease constituted the normal control group. Each HCM patient was matched to a control subject with respect to age ( 2 years), sex, and body surface area ( 10%). A separate cohort comprised 15 asymptomatic gene-positive/phenotype-negative relatives (age, years; range, 12 to 57 years; 60% men) who were identified in HCM families from the participating centers, and each was genotyped to a HCM disease-causing sarcomere protein mutation: myosin binding protein C mutation in 11, -myosin heavy chain in 2, and troponin T in 2, with a maximal LV wall thickness of 12 mm, within the normal range relative to body surface area and age, and in the absence of LV outflow tract obstruction. Mitral valve dimensions in each gene-positive/phenotype-negative patient were matched to those of a control subject with respect to age and body surface area, as described for the primary study group of 172 patients. In HCM patients, LV outflow tract obstruction was defined by continuous-wave Doppler echocardiography as a peak instantaneous outflow gradient of 30 mm Hg under resting conditions 11,12 resulting from marked mitral valve systolic anterior motion with anterior mitral leaflet-septal contact. 11 In patients without obstruction at rest (gradient 30 mm Hg), provocable gradients were defined as 30 mm Hg immediately after exercise, occurring in 42 of the 102 patients undergoing standard Bruce treadmill protocol. 12 Patients with substantial LV remodeling and the end-stage phase of HCM (ie, ejection fraction 50%) 13 and patients with previous alcohol septal ablation or surgical septal myectomy were excluded. In addition, no patient had mitral valve prolapse, 14 evidence of other intrinsic mitral valve disease, or confirmed anomalous insertion of anterolateral papillary muscle directly into anterior mitral leaflet. 15 Written informed consent was obtained from all study patients as approved by the Internal Review Board of the respective participating institutions, agreeing to use of their medical information for research purposes. Cardiovascular Magnetic Resonance CMR imaging was performed (Tufts Medical Center: Philips Gyroscan ACS-NT 1.5T, Best, the Netherlands; Minneapolis Heart Institute: Siemens Sonata 1.5 T, Erlangen, Germany) with an ECG gated steady-state, free precession breath-hold cines in 3 long-axis planes and sequential 10-mm short-axis slices from the atrioventricular ring to apex. LV volumes, mass, and ejection fraction were measured with standard volumetric techniques and analyzed with commercially available software (MASS, version 6.1.6, Medis, Inc, the Netherlands). Left ventricular volume and mass data were indexed to body surface area. Maximum end-diastolic LV wall thickness measurements in each of the 16 segments were automatically calculated by commercially available software. Late-gadolinium-enhancement images were acquired 10 to 15 minutes after intravenous administration of 0.2 mmol/kg gadolinium-dtpa (Magnevist, Schering, Berlin, Germany), with breath-held segmented inversion-recovery sequence acquired in the same orientations as the cine images. A threshold 6 SDs exceeding the mean for nonenhanced myocardium was used to define areas of late gadolinium enhancement. 16 Anterior mitral leaflet (AML) and posterior mitral leaflet (PML) lengths were measured in diastole in only the 3-chamber view, with the leaflets maximally extended parallel to the anterior septum and LV free wall (Figure 1). The 3-chamber view was derived from an end-systolic short-axis view with the slice plane oriented along the aortic root parallel to the LV (ie, aortic) outflow tract. Leaflet length was defined as the distance from the most distal extent of anterior leaflet to its insertion into the posterior aortic wall and the most distal extent of posterior leaflet into the basal LV posterior free wall. Demarcation of mitral valve leaflet tip and contiguous chordae tendinae was made by visual inspection of valve motion during real-time analysis of the 3-chamber view cine, with measurements made in stop-frame mode using the internal calibration. Transverse LV outflow tract diameter was measured 1 cm below the aortic valve plane on the 3-chamber view image at end systole. The ratio of the transverse LV outflow tract diameter to AML length was constructed (range, 0.8 to 5.2; mean, 1.6). Reproducibility Interobserver and intraobserver variabilities for the measurement of mitral valve leaflet lengths were assessed in a subset of 30 randomly selected CMR studies from the HCM cohort of 172 patients. For interobserver variability, 2 readers (C.H. and M.S.M.) independently measured anterior and posterior mitral valve leaflet lengths without prior knowledge of the clinical data, and were blinded to the previous

3 42 Circulation July 5, 2011 Table. Demographics and Cardiac Magnetic Resonance Findings in Hypertrophic Cardiomyopathy Patients, Genotype-Positive/Phenotype-Negative Hypertrophic Cardiomyopathy Family Members, and Control Subjects HCM Patients Control Subjects P Genotype-Positive/ Phenotype-Negative HCM Patients Control Subjects P Patients, n Age at enrollment, y Men, n (%) 106 (62) 106 (62) (47) 7 (47) 1.0 Body surface area, m Anterior leaflet length, mm Posterior leaflet length, mm LVOT diameter, mm LV ejection fraction, % Maximum LV thickness, mm HCM indicates hypertrophic cardiomyopathy; LV, left ventricular; and LVOT, LV outflow tract. morphometric results. For intraobserver variability, 1 reader (C.H.) independently measured mitral valve leaflet lengths in an identical fashion on 2 occasions (6 months apart) while blinded to the clinical data. Statistical Analysis Continuous data are summarized as mean SD. For comparison of normally distributed data, a paired t test or 1-way or 2-way ANOVA was used as appropriate. A 2 test was used to compare categorical variables expressed as proportions. All P values are 2 sided and considered significant when When required, we provided P values after Bonferroni correction. Relationships between mitral leaflet length and other continuous variables were assessed by correlation analysis. Predictors of LV outflow obstruction were analyzed by stepwise (forward conditional) multivariable logistic regression analysis with the following variables: LV outflow tract diameter, LV end-diastolic dimension, ejection fraction, outflow tract velocity, basal ventricular septal thickness and anterior mitral valve leaflet length. Calculations were performed with SPSS 12.0 software (SPSS Inc, Chicago, IL). All authors had full access to and take full responsibility for the integrity of the data. All authors have agreed to the manuscript as written. Results Patient Characteristics Clinical and demographic characteristics of the 172 HCM study patients and control subjects are summarized in the Table. Mean age at evaluation was years (range, 8 to 86 years); 106 patients (62%) were men. At the time of CMR study, 103 patients (60%) were asymptomatic in New York Heart Association functional class I, 45 (26%) had mild symptoms in class II, and 24 (14%) had severe heart failure symptoms in class III or IV. Left ventricular ejection fraction was 71 9% (range, 58% to 89%). Left ventricular outflow gradients 30 mm Hg at rest (range, 30 to 117 mm Hg) were present in 35 patients (20%), and a provocable (ie, exerciseinduced) gradient was present in 42 other patients. Mitral Valve Morphology In HCM patients, AML length was 26 5 mm (range, 17 to 41 mm), significantly greater than in control subjects (19 5 mm; range, 8 to 29 mm; P 0.001). The PML length in HCM was 14 4 mm (range, 6 to 28 mm), also significantly exceeding that of matched control subjects (10 3 mm; range, 2 to 17 mm; P 0.001; the Table). In 59 of the 172 HCM patients (34%), lengths of the AML alone (n 21; 12%), the PML alone (n 18; 10%), or both (n 20; 12%) exceeded 2 SDs from the mean of the control group (ie, 30 and 17 mm, respectively). The AML and PML leaflet lengths were greater among HCM patients than control subjects across virtually all age groups (all adjusted P ; Figure 2), including children 15 to 20 years of age (AML, 26 5 versus 21 4 mm; P ) and older patients 60 years of age (AML, 26 4 versus 19 2 mm; P ). No differences in leaflet length were evident among HCM patients with respect to severity of mitral regurgitation (absent to mild [0 to 1 ], 26 4 mm; moderate [2 ], 25 5 mm; marked [3 to 4 ], 26 4 mm; P 0.2 for AML), New York Heart Association class (overall P 0.45 for AML; P 0.94 for PML), or sex (P 0.32). Relation of Mitral Valve Morphology to Left Ventricular Hypertrophy and Late Gadolinium Enhancement Among HCM patients, no relationship was evident between AML length and either LV mass index or maximal wall thickness (P 0.09 and P 0.16, respectively; Figures 3 and 4). Similarly, there was no relation between PML length and mass index or wall thickness (P 0.9 and P 0.5, respectively; Figures 3 and 4). The AML length did not differ between the 32 patients with mild LV hypertrophy (thickness, 18 mm) and 15 patients with extreme LV hypertrophy (thickness, 30 mm): 25 5 versus 26 5 mm, respectively (P 0.78). In addition, 7 of the 32 patients (22%) with mild hypertrophy had markedly elongated mitral leaflets ( 30 mm in length) compared with 3 patients (20%) with extreme LV hypertrophy (P 0.5). Late gadolinium enhancement was present in 83 HCM patients (48%). No differences were evident in either AML or PML leaflet length with respect to the presence or absence of late gadolinium enhancement (AML, 27 5 versus 26 4, P 0.33; PML, 14 4 versus 14 3 mm, P 0.9). Relation of Mitral Valve Morphology and Left Ventricular Outflow Tract Obstruction There was no difference in AML or PML length among HCM patients with or without LV outflow tract gradients

4 Maron et al Mitral Valve Abnormalities in HCM 43 Figure 2. Distribution of anterior mitral leaflet (AML; top) and posterior mitral leaflet (PML; bottom) lengths in 172 hypertrophic cardiomyopathy (HCM) patients compared with 172 normal control subjects. P values are after Bonferroni adjustment. *P comparing HCM and control patients in each age group tertile; P 1.00 comparing HCM patients 14 years of age and control patients. 30 mm Hg at rest (AML, 27 4 versus 26 5 mm, P 0.57; PML, 15 4 versus 14 4 mm, P 0.15), nor was there a correlation in the overall HCM group between AML or PML length and the magnitude of LV outflow gradient at rest (AML, P 0.10; PML, P 0.12). Neither AML (P 0.27) or PML (P 0.5) length nor any other morphological variable was an independent predictor of outflow obstruction at rest. In addition, neither AML length nor PML length differed among HCM patients with LV outflow tract gradients 30 mm Hg induced by exercise and those patients with rest gradients 30 mm Hg (AML, 26 5 versus 27 4 mm, P 0.4; PML, 14 3 versus 15 4 mm, P 0.3). However, a ratio of AML length to transverse LV outflow tract diameter of 2.0 was significantly more common in patients with outflow gradients 30 mm Hg at rest (16 of 35, 46%) than in patients without obstruction (20 of 137, 15%; P 0.001; Figure 5). The ratio of mean AML length to outflow tract diameter was also significantly greater in HCM patients with gradients 30 mm Hg at rest than in those without rest obstruction ( versus ; P 0.003). The ratio of mean AML length to outflow tract diameter showed a relatively weak but significant relation to magnitude of outflow gradient (P 0.01). Genotype-Positive/Phenotype-Negative HCM Patients Clinical and demographic characteristics of the 15 asymptomatic genotype-positive/phenotype-negative patients are summarized in the Table. The AML in these patients was significantly longer than in normal control subjects of the same age and body surface area (21 3 versus 18 3 mm, respectively; P 0.01; Figure 1), with no difference in PML length (11 2 versus 10 2 mm, respectively; P 0.17). The Figure 3. Relation between anterior mitral leaflet (AML) and posterior mitral leaflet (PML) lengths and maximal left ventricular (LV) wall thickness among 172 hypertrophic cardiomyopathy (HCM) patients. *P comparing AML and PML among HCM patients for maximal LV wall thickness categories; P 0.05 comparing AML and PML lengths among HCM patients for maximal LV wall thickness of 22 to 23 mm.

5 44 Circulation July 5, 2011 Figure 4. Scatterplot showing the relation between maximal left ventricular (LV) wall thickness and anterior mitral leaflet (AML; A) and posterior mitral leaflet (PML; B) lengths in 172 hypertrophic cardiomyopathy patients at the time of clinical evaluation and cardiovascular magnetic resonance imaging. AML length in HCM patients with LV hypertrophy exceeded that of preclinical patients (P 0.001). Reproducibility of Mitral Valve Leaflet Measurements Interobserver variability showed small differences in the measurements of AML and PML lengths between the 2 observers ( 0.6 to 1.8 and 2.9 to 5.6, respectively). Analysis of intraobserver variability also showed small differences in the measurements of AML and PML lengths with an intraclass correlation coefficient of 0.5 for the AML and 0.6 for the PML. Discussion Since the initial contemporary report 50 years ago, the phenotypic expression of HCM has been reported largely in terms of LV hypertrophy and the cardiac sarcomere. 1 5,17,18 However, a number of morphological features of HCM appear unrelated to disease-causing sarcomere mutations, including LV apical aneurysms, structurally abnormal intramural coronary arteries responsible for microvascular ischemia, segmental increase in LV wall thickness confined to only a portion of the chamber, and anomalous insertion of anterolateral papillary muscle into the mitral valve. 15,19 22 In addition, previous studies of mitral valves removed at surgery or autopsy in relatively small and selected HCM subgroups have suggested that the mitral valve leaflets may be elongated in some patients, although these studies were compromised by inadequate controls. 6,7 Therefore, in the present investigation, we have taken the opportunity to use CMR imaging, with its high spatial and temporal resolution, to characterize the morphology of the mitral valve and its relation to a number of demographic and clinical variables in a large consecutive HCM cohort. Our data demonstrate that mitral valve leaflet length is significantly increased in HCM patients compared with an age-, sex-, and body size matched control population without cardiovascular disease. In fact, in 30% of patients with HCM, elongation of the AML and/or PML was substantial, exceeding that of matched control subjects by 2 SDs. Furthermore, the mitral leaflet lengths reported here by CMR are virtually identical to the ex vivo measurements of valves excised from Figure 5. Relation between the ratio of anterior mitral leaflet (AML) length to left ventricular (LV) outflow tract (LVOT) diameter and gradients. A and B, Threechamber diastolic cardiac magnetic resonance frames from a 26-year-old woman with (A) greatly elongated AML (34 mm; arrows) and relatively mild ventricular septal thickening (VS; 17 mm). In the same patient, an end-systolic image (B) demonstrates a small LVOT with a transverse diameter of 15 mm (brackets; AML length/lvot diameter, 2.3) and systolic anterior motion with mitral-septal contact (arrow). The LVOT gradient was 90 mm Hg, and the greatly elongated AML was plicated at surgery to reduce excursion and systolic anterior motion. C, Bar graph showing the relation of LVOT gradient to the ratio of AML length to LVOT diameter 2.0. AO indicates aorta; LA, left atrium; and HCM, hypertrophic cardiomyopathy.

6 Maron et al Mitral Valve Abnormalities in HCM 45 HCM patients postmortem or after surgical mitral valve replacement. 6 In addition, those morphological studies demonstrated that mitral leaflet length was representative of total valve tissue area. Hence, it is reasonable to assume that CMR provides a reliable in vivo estimate of overall mitral valve size. Our data also support the principle that morphological abnormalities of the mitral valve represent a primary phenotypic expression of HCM. Mitral valve leaflet elongation proved to be independent of a number of demographic and clinical variables relevant to HCM disease expression, including sex and heart failure symptoms. Leaflet length was also unrelated to patient age, and in fact was increased early in life; ie, in preadolescent HCM patients the lengths of both the AML and PML significantly exceeded that in age-, sex-, and body size matched control subjects. In addition, not only was a significant relationship between mitral leaflet length and LV wall thickness (or mass) absent, but we also identified a subset of HCM patients with a unique phenotype in whom hypertrophy was particularly mild while the mitral valve was disproportionately enlarged with prominent leaflet elongation. Furthermore, we found no evidence that hemodynamic factors were responsible for the observed mitral valve structural abnormalities, given the similarity in leaflet lengths between HCM patients with or without LV outflow obstruction. Finally, the observation that anterior mitral valve leaflet lengths were greater among young preclinical HCM patients without LV hypertrophy than in normal control subjects further supports the principle that increased mitral valve size represents an independent and primary component of HCM disease expression. Although the precise pathogenesis for elongation of the mitral valve leaflets in patients with HCM is uncertain, our findings, including the absence of myocytes from the leaflets, suggest that disease-causing mutations encoding proteins of the cardiac sarcomere 17 are unlikely to account for the entire phenotypic expression of HCM. Indeed, other disease variables such as modifier genes and environmental factors 17,23,24 may well play a role in the development of certain morphological abnormalities observed in HCM, including mitral valve enlargement. Although increased mitral valve leaflet length was identified in some children (as young as 13 years of age), our study design did not permit determination of whether mitral valve enlargement in HCM can represent a congenital malformation. Increased mitral leaflet length proved to be an important, although not the sole determinant of LV outflow obstruction in our HCM patients. Indeed, on the basis of our analyses, the mechanism responsible for subaortic gradients is multifactorial, given that no single disease variable or outflow tract component tested in our multivariable model proved to be an independent predictor of rest outflow obstruction. However, LV geometry in which anterior mitral leaflet length exceeded 2-fold the transverse dimension of the outflow tract at end systole was an important morphological abnormality responsible for outflow obstruction at rest The observation that mitral valve length is associated with outflow obstruction in some patients has implications for management strategies in this disease Elongated mitral leaflets create 2 potential problems. First, the mitral-septal contact point (and site of subaortic obstruction) can be displaced distal to its usual position, creating the necessity for an extended muscular resection ,40 Second, an extremely elongated AML has the theoretical potential to produce mitral-septal contact (and obstruction) even after apparently adequate septal muscular resection. Indeed, a number of surgical reports of severely symptomatic obstructive HCM patients promote the combined approach of septal myectomy and AML repair, with leaflet extension or shortening reconstruction or plication. 31,32,37,39,41 In this regard, van der Lee et al 37 reported that 90% of their operated patients over an 8-year period were judged by the surgeon to have particularly elongated mitral leaflets that would have made myectomy alone unlikely to yield optimal hemodynamic results. Taken together, these historical observations and the present data suggest that CMR assessment of mitral leaflet length may have a significant role in preoperative strategic planning to identify those HCM patients in whom mitral valve size and leaflet length can affect surgical management. Intraoperative decision-making with regard to LV outflow tract morphology may also rely on observations made with transesophageal echocardiography. 42,43 Finally, identification of elongated mitral valve leaflets by CMR can represent a clinical marker in HCM family members without LV hypertrophy (in whom the genotype is unknown). 44,45 This assertion is substantiated by our data in genotype-positive/phenotype-negative relatives showing that mitral leaflet elongation was the sole overt clinical manifestation of an HCM-causing sarcomere protein mutation. 45 Identification of an elongated mitral valve leaflet by CMR in such individuals also underscores the potential value of genotyping to achieve a definitive HCM diagnosis. 45 These observations support an expanded role for CMR in earlier clinical diagnosis of relatives affected by HCM, 20,46,47 although we recognize that it is also possible to appreciate greatly elongated mitral valve leaflets qualitatively by visual inspection with 2-dimensional echocardiography. Conclusions In this large HCM cohort, CMR demonstrates AML and PML elongation independently of other clinical variables of disease expression. These findings suggest that morphological valvular abnormalities likely represent a primary phenotypic expression of this complex disease, implying that basic molecular pathways other than (and/or in addition to) the disease-causing sarcomere mutation play a role in the development of HCM disease expression. In addition, elongated mitral valves in HCM may affect diagnosis and management considerations. Specifically, the enlarged mitral valve can represent a morphological marker for this disease, ultimately aiding in the identification of patients with an otherwise ambiguous diagnosis, including genetically affected HCM family members without LV hypertrophy. Elongated mitral leaflets (in association with small outflow tract diameter) represent a major contributor to dynamic LV outflow tract obstruction and may affect the selection of patients for the most appropriate septal reduction treatment strategy.

7 46 Circulation July 5, 2011 Sources of Funding This work was supported in part by a grant from the Heorst Foundations (San Francisco, CA) to Dr B.J. Maron. Disclosures Dr M.S. Maron has been a consultant to PGx Health. Dr B.J. Maron has been a consultant to Gene Dx. The other authors report no conflicts. References 1. Braunwald E, Lambrew CT, Rockoff SD, Ross J Jr, Morrow AG. Idiopathic Hypertrophic subaortic stenosis, I: a description of the disease based upon an analysis of 64 patients. Circulation. 1964;30:(suppl IV): IV-3 IV Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J Cardiovasc Electrophysiol. 2008;19: Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287: Maron BJ, McKenna WJ, Danielson GK, Kappenberger CJ, Kahn HJ, Seidman CE, Shah PM, Spencer WH, Spirito P, Ten Cate FJ, Wigle ED. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol. 2003;42: Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy: clinical spectrum and treatment. Circulation. 1995;92: Klues HG, Maron BJ, Dollar AL, Roberts WC. Diversity of structural mitral valve alterations in hypertrophic cardiomyopathy. Circulation. 1992;85: Klues HG, Proschan MA, Dollar AL, Spirito P, Roberts WC, Maron BJ. Echocardiographic assessment of mitral valve size in obstructive hypertrophic cardiomyopathy: anatomic validation from mitral valve specimen. Circulation. 1993;88: Lima JA, Desai MY. Cardiovascular magnetic resonance imaging: current and emerging applications. J Am Coll Cardiol. 2004;44: Pennell DJ. Cardiovascular magnetic resonance. Circulation. 2010;121: Han Y, Peters DC, Salton CJ, Byzmek D, Nezafat R, Goddu B, Kissinger KV, Zimetbaum PJ, Manning WJ, Yeon SB. Cardiovascular magnetic resonance characterization of mitral valve prolapse. J Am Coll Cardiol Cardiovasc Imaging. 2008;1: Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003; 348: Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114: Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, Mackey-Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation. 2006;114: Petrone RK, Klues HG, Panza JA, Peterson EE, Maron BJ. Coexistence of mitral valve prolapse in a consecutive group of 528 patients with hypertrophic cardiomyopathy assessed with echocardiography. J Am Coll Cardiol. 1992;20: Klues HG, Roberts WC, Maron BJ. Anomalous insertion of papillary muscle directly into anterior mitral leaflet in hypertrophic cardiomyopathy: significance in producing left ventricular outflow obstruction. Circulation. 1991;84: Harrigan CJ, Maron MS, Maron BJ, Peters DC, Gibson CM, Manning WJ, Appelbaum E. Accuracy and reproducibility of quantifying myocardial fibrosis in hypertrophic cardiomyopathy using delayed enhancement cardiovascular magnetic resonance techniques. Radiology. 2011;258: Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001;104: Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, Ommen SR, Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C, Torricelli F, Cecchi F. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2008;83: Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med. 2003;349: Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I, Biller L, Lesser JR, Udelson JE, Manning WJ, Appelbaum E. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol. 2009;54: Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS, Lesser JR, Udelson JE, Ackerman MJ, Maron BJ. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation. 2008;118: Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Girolami F, Torricelli F, Camici PG. Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006;47: Perkins MJ, Van Driest SL, Ellsworth EG, Will ML, Gersh BJ, Ommen SR, Ackerman MJ. Gene-specific modifying effects of pro-lvh polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy. Eur Heart J. 2005;26: van der Merwe L, Cloete R, Revera M, Heradian M, Goosen A, Corfield VA, Brink PA, Moolman-Smook JC. Genetic variation in angiotensinconverting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy. Hum Genet. 2008;124: Klues HG, Roberts WC, Maron BJ. Morphological determinants of echocardiographic patterns of mitral valve systolic anterior motion in obstructive hypertrophic cardiomyopathy. Circulation. 1993;87: Levine RA, Vlahakes GJ, Lefebvre X, Guerrero JL, Cape EG, Yoganathan AP, Weyman AE. Papillary muscle displacement causes systolic anterior motion of the mitral valve: experimental validation and insights into the mechanism of subaortic obstruction. Circulation. 1995;91: Sherrid MV, Chaudhry FA, Swistel DG. Obstructive hypertrophic cardiomyopathy: echocardiography, pathophysiology, and the continuing evolution of surgery for obstruction. Ann Thorac Surg. 2003;75: Sherrid MV, Chu CK, Delia E, Mogtader A, Dwyer EM Jr. An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1993;22: He S, Hopmeyer J, Lefebvre XP, Schwammenthal E, Yoganathan AP, Levine RA. Importance of leaflet elongation in causing systolic anterior motion of the mitral valve. J Heart Valve Dis. 1997;6: Jiang L, Levine RA, King ME, Weyman AE. An integrated mechanism for systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy based on echocardiographic observations. Am Heart J. 1987; 113: Balaram SK, Sherrid MV, Derose JJ Jr, Hillel Z, Winson G, Swistel DG. Beyond extended myectomy for hypertrophic cardiomyopathy: the resection-plication-release (RPR) repair. Ann Thorac Surg. 2005;80: Balaram SK, Tyrie L, Sherrid MV, Afthinos J, Hillel Z, Winson G, Swistel DG. Resection-plication-release for hypertrophic cardiomyopathy: clinical and echocardiographic follow-up. Ann Thorac Surg. 2008; 86: Kofflard MJ, van Herwerden LA, Waldstein DJ, Ruygrok P, Boersma E, Taams MA, Ten Cate FJ. Initial results of combined anterior mitral leaflet extension and myectomy in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 1996;28: Maron BJ, Dearani JA, Ommen SR, Maron MS, Schaff HV, Gersh BJ, Nishimura RA. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44: Minakata K, Dearani JA, Nishimura RA, Maron BJ, Danielson GK. Extended septal myectomy for hypertrophic obstructive cardiomyopathy with anomalous mitral papillary muscles or chordae. J Thorac Cardiovasc Surg. 2004;127:

8 Maron et al Mitral Valve Abnormalities in HCM Schoendube FA, Klues HG, Reith S, Flachskampf FA, Hanrath P, Messmer BJ. Long-term clinical and echocardiographic follow-up after surgical correction of hypertrophic obstructive cardiomyopathy with extended myectomy and reconstruction of the subvalvular mitral apparatus. Circulation. 1995;92:II van der Lee C, Kofflard MJ, van Herwerden LA, Vletter WB, ten Cate FJ. Sustained improvement after combined anterior mitral leaflet extension and myectomy in hypertrophic obstructive cardiomyopathy. Circulation. 2003;108: Schwammenthal E, Levine RA. Dynamic subaortic obstruction: a disease of the mitral valve suitable for surgical repair? J Am Coll Cardiol. 1996;28: McIntosh CL, Maron BJ. Current operative treatment of obstructive hypertrophic cardiomyopathy. Circulation. 1988;78: Yacoub MH. Surgical versus alcohol septal ablation for hypertrophic obstructive cardiomyopathy: the pendulum swings. Circulation. 2005; 112: McIntosh CL, Maron BJ, Cannon RO 3rd, Klues HG. Initial results of combined anterior mitral leaflet plication and ventricular septal myotomy-myectomy for relief of left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Circulation. 1992;86:II Grigg LE, Wigle ED, Williams WG, Daniel LB, Rakowski H. Transesophageal Doppler echocardiography in obstructive hypertrophic cardiomyopathy: clarification of pathophysiology and importance in intraoperative decision making. J Am Coll Cardiol. 1992;20: Ommen SR, Park SH, Click RL, Freeman WK, Schaff HV, Tajik AJ. Impact of intraoperative transesophageal echocardiography in the surgical management of hypertrophic cardiomyopathy. Am J Cardiol. 2002;90: Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, Seidman CE. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol. 2001;38: Ho CY, Seidman CE. A contemporary approach to hypertrophic cardiomyopathy. Circulation. 2006;113:e858 e Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse N, Weil J, Zenovich AG, Maron BJ. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation. 2005;112: Maron MS, Lesser JR, Maron BJ. Management implications of massive left ventricular hypertrophy in hypertrophic cardiomyopathy significantly underestimated by echocardiography but identified by cardiovascular magnetic resonance. Am J Cardiol. 2010;105: CLINICAL PERSPECTIVE Mutations in genes encoding proteins of the cardiac sarcomere are responsible for left ventricular hypertrophy, the diagnostic sine qua non of hypertrophic cardiomyopathy (HCM). However, whether other morphological features of HCM, seemingly unrelated to sarcomere mutations, are part of the disease phenotype is uncertain. We used cardiovascular magnetic resonance to characterize mitral valve abnormalities in a cohort of patients with HCM. Both anterior and posterior mitral valve leaflet lengths were greater among HCM patients compared with an age- and sex-matched control population (26 5 versus 19 5 mm, P 0.001; and 14 4 versus 10 3 mm, P 0.001, respectively), including more than one third of HCM patients in whom one or both of the mitral leaflets were substantially increased in length. In HCM patients, there was no relationship between mitral valve leaflet length and a number of clinical and demographic variables, including age, maximal left ventricular wall thickness, or left ventricular mass. In addition, elongated mitral valve leaflets were often the only clinical manifestation present in HCM family members carrying a sarcomere mutation without left ventricular hypertrophy and can represent the sole clinical marker of genotype-positive status. Elongated mitral valve leaflets were an important determinant of left ventricular outflow obstruction, particularly in patients in whom anterior mitral leaflet length exceeded 2-fold the transverse dimension of the outflow tract. These cardiovascular magnetic resonance based observations show that structural abnormalities of the mitral valve represent a primary expression of the HCM phenotype and a morphological marker that may aid in diagnostic and management strategies, including optimal planning for septal reduction therapy.